Effect of Oral Probenecid Coadministration on the Chronic Toxicity and Pharmacokinetics of Intravenous Cidofovir in Cynomolgus Monkeys

• Published in: Toxicological sciences Vol. 44; no. 2; pp. 97 - 106
• Main Authors: Lacy, Steven A., Hitchcock, Michael J. M., Lee, William A., Tellier, Pierre, Cundy, Kenneth C.
• Format: Journal Article
• Language: English
• Published: Cary, NC Oxford University Press 01.08.1998
• Subjects: Administration, Oral; Animals; Antiviral Agents - toxicity; biological activity; Biological and medical sciences; Cidofovir; Cidofovir injection (Vistide); Cytosine - analogs & derivatives; Cytosine - pharmacokinetics; Cytosine - toxicity; Drug toxicity and drugs side effects treatment; Female; Injections, Intravenous; Kidney - drug effects; Kidney - pathology; l-[(S)-3-hydroxy-2-phosphonomethoxy)propyl]cyto-sine; Macaca fascicularis; Male; Medical sciences; nucleotide analogue with antiherpesvirus activity; Organ Size - drug effects; Organophosphonates; Organophosphorus Compounds - pharmacokinetics; Organophosphorus Compounds - toxicity; Pharmacology. Drug treatments; Probenecid - pharmacology; Toxicity: urogenital system; Acyclic nucleoside; Urinary system disease; Intravenous administration; Toxicity; Monkey; Oral administration; Cidofovir; Uricosuric agent; Kidney; Prevention; Toxicokinetics; Vertebrata; Chronic; Mammalia; Cytoprotector; Animal; Primates; Antiviral; Kinetics; Pharmacokinetics; Pyrimidine nucleotide; Probenecid
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/44.2.97

In animals and humans, intravenous administration of the antiviral nucleotide analogue cidofovir results in a dose-limiting nephrotoxicity characterized by damage to the proximal tubular epithelial cells. Probenecid, a competitive inhibitor of organic anion transport in the proximal tubular epithelial cells, was evaluated for its effect on the chronic toxicity and pharmacokinetics of cidofovir. Cynomolgus monkeys (5/sex/group) received cidofovir for 52 consecutive weeks as a once weekly intravenous bolus injection at 0 (saline), 0.1, 0.5, or 2.5 mg/kg/dose alone or at 2.5 mg/kg/dose in combination with probenecid (30 mg/kg/dose via oral gavage 1 h prior to cidofovir administration). Cidofovir-associated histopathological changes were seen only in the kidneys, testes, and epididymides. Nephrotoxicity (mild to moderate cortical tubular epithelial cell karyomegaly, tubular dilatation, basement membrane thickening) was present only in monkeys receiving 2.5 mg/kg/dose cidofovir without probenecid. The incidence and severity of testicular (hypo- and aspermatogenesis) and epididymal (severe oligo- and aspenmia) changes were increased in monkeys administered cidofovir at 2.5 mg/kg/dose, either alone or in combination with oral probenecid. Renal drug clearance was decreased between Weeks 1 and 52 in the 2.5 mg/kg/dose groups and resulted in an increased systemic exposure to cidofovir (as measured by AUC) that was significantly greater in monkeys administered cidofovir alone (312% increase in males, 98% in females) than in those coadministered probenecid (32% increase in males, 3% in females). These results demonstrate that oral probenecid coadministration protects against the morphological evidence of nephrotoxicity and the accompanying decrease in renal clearance in monkeys receiving chronic intravenous cidofovir treatment.